title: Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance.
abstract: Breast Cancer Type 1 Susceptibility Protein (BRCA1)-deficient cells have compromised DNA repair and are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. Despite initial responses, the development of resistance limits clinical efficacy. Mutations in the BRCA C-terminal (BRCT) domain of BRCA1 frequently create protein products unable to fold that are subject to protease-mediated degradation. Here, we show HSP90-mediated stabilization of a BRCT domain mutant BRCA1 protein under PARP inhibitor selection pressure. The stabilized mutant BRCA1 protein interacted with PALB2-BRCA2-RAD51, was essential for RAD51 focus formation, and conferred PARP inhibitor as well as cisplatin resistance. Treatment of resistant cells with the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin reduced mutant BRCA1 protein levels and restored their sensitivity to PARP inhibition. Resistant cells also acquired a TP53BP1 mutation that facilitated DNA end resection in the absence of a BRCA1 protein capable of binding CtIP. Finally, concomitant increased mutant BRCA1 and decreased 53BP1 protein expression occur in clinical samples of BRCA1-mutated recurrent ovarian carcinomas that have developed resistance to platinum. These results provide evidence for a two-event mechanism by which BRCA1-mutant tumors acquire anticancer therapy resistance.
authors.affiliation: Departments of Medical Oncology, Radiation Oncology, and Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215.
authors.forename: Neil
authors.initials: N
authors.lastname: Johnson
authors.forename: Shawn F
authors.initials: SF
authors.lastname: Johnson
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Li
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Choi
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bernhardy
authors.forename: Yifan
authors.initials: Y
authors.lastname: Wang
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.forename: Kristopher A
authors.initials: KA
authors.lastname: Sarosiek
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Moreau
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chowdhury
authors.forename: Anneka
authors.initials: A
authors.lastname: Wickramanayake
authors.forename: Maria I
authors.initials: MI
authors.lastname: Harrell
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.forename: Alan D
authors.initials: AD
authors.lastname: D'Andrea
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Swisher
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D000076164:Fanconi Anemia Complementation Group N Protein; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010984:Platinum / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D016227:Benzoquinones; D000076164:Fanconi Anemia Complementation Group N Protein; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009687:Nuclear Proteins; C512790:PALB2 protein, human; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D025521:Tumor Suppressor Proteins; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D010984:Platinum; D011065:Poly(ADP-ribose) Polymerases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin
keywords: cancer therapy; homologous recombination